Increased environmental exposure to iodine from dietary or therapeutic sources may contribute to the escalating prevalence of autoimmune thyroiditis in humans. Highly iodinated thyroglobulin, the 660 Kd glycoprotein major storage form of thyroid hormones, due to increased iodine intake, has been associated with increased incidence and severity of spontaneous autoimmune thyroiditis in chickens and in the diabetes- prone lymphocytic thyroiditis-associated BB/W rat. Clinical observations in humans also associate excess iodine as a potentiator of autoimmune thyroid disease, but no experimental information about the pathogenesis in humans is available. The role of iodine in a multifactorial autoimmune disease like chronic lymphocytic thyroiditis is a factor that has too frequently been neglected and may account for many of the differences in frequency of autoimmune thyroid disease among geographical areas. We propose to explore the differences in the immune response to thyroglobulin and its fragments iodinated to varying degrees between patients suffering from autoimmune thyroid disease compared to euthyroid individuals with thyroid autoantibodies. First, studies will concentrate on the preparation, iodination, isolation, and identification of the relevant thyroglobulin and its fragments. Tryptic- digest peptide maps resolved by HPLC will enable us to compare patterns of iodination among the various Tg preparations. Second, we propose, to evaluate cellular human immune response to variously iodinated thyroglobulin or its fragments. The functional responses of human lymphocytes to variously iodinated thyroglobulin and its fragments will be tested by means of cell proliferation assays. We will develop a series of T cell lines/clones to test the fine specificities of the cellular response. We will then investigate markers of cellular proliferation (e.g. IL-2, IL-4 secretion) to pinpoint the specific stage at which the thyroglobulin or its fragments is playing a role. The ultimate goal is to understand the immunotoxic role of iodine in inducing autoimmune thyroid disease with the hope of developing preventive strategies.